Originally published as JCO Early Release 10.1200/JCO.2006.08.4251 on February 12 2007

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Specific Secondary Genetic Alterations in Mantle Cell Lymphoma Provide Prognostic Information Independent of the Gene Expression–Based Proliferation Signature

Itziar Salaverria, Andreas Zettl, Sílvia Beà, Victor Moreno, Joan Valls, Elena Hartmann, German Ott, George Wright, Armando Lopez-Guillermo, Wing C. Chan, Dennis D. Weisenburger, Randy D. Gascoyne, Thomas M. Grogan, Jan Delabie, Elaine S. Jaffe, Emili Montserrat, Hans-Konrad Muller-Hermelink, Louis M. Staudt, Andreas Rosenwald, Elias Campo

From the Department of Pathology and Hematology, Hospital Clinic, University of Barcelona; Cancer Epidemiology Service, Institut d’Investigació Biomedica de Bellvitge, Catalan Institute of Oncology and Laboratori d'Estadistica i Epidemiologia, Autonomous University of Barcelona; Department of Statistics, E.T.S.E.I.B. Polytechnics University of Barcelona, Barcelona, Spain; Department of Pathology, University of Würzburg, Würzburg, Germany; Biometric Research, Metabolism and Pathology Branch, National Cancer Institute, and Bioinformatics and Molecular Analysis Section, Computational Bioscience and Engineering Laboratory, Center for Information Technology, National Institutes of Health, Bethesda, MD; Departments of Pathology and Microbiology, and Internal Medicine, University of Nebraska Medical Center, Omaha, NE; Department of Pathology, Netherlands Cancer Center, Amsterdam, the Netherlands; Department of Pathology and Division of Medical Oncology, University of British Columbia and British Columbia Cancer Agency, Vancouver, British Columbia, Canada; Southwest Oncology Group, Oregon Health and Science University, Portland, OR; Departments of Pathology and Medicine, University of Arizona Cancer Center, Tucson, AZ; James P. Wilmot Cancer Center, University of Rochester School of Medicine, Rochester, NY; and Departments of Immunology, Oncology, and Pathology, Rikshospitalet-Radiumhospitalet, Medical Center and University of Oslo, Oslo, Norway

Address reprint requests to Elias Campo, MD, Hematopathology Section, Hospital Clinic, Villarroel 170, 08036-Barcelona, Barcelona, Spain; e-mail: ecampo{at}clinic.ub.es

Purpose: To compare the genetic relationship between cyclin D1–positive and cyclin D1–negative mantle cell lymphomas (MCLs) and to determine whether specific genetic alterations may add prognostic information to survival prediction based on the proliferation signature of MCLs.

Patients and Methods: Seventy-one cyclin D1–positive and six cyclin D1–negative MCLs previously characterized by gene expression profiling were examined by comparative genomic hybridization (CGH).

Results: Cyclin D1–negative MCLs were genetically characterized by gains of 3q, 8q, and 15q, and losses of 1p, 8p23-pter, 9p21-pter, 11q21-q23, and 13q that were also the most common alterations in conventional MCLs. Parallel analysis of CGH aberrations and locus-specific gene expression profiles in cyclin D1–positive patients showed that chromosomal imbalances had a substantial impact on the expression levels of the genes located in the altered regions. The analysis of prognostic factors revealed that the proliferation signature, the number of chromosomal aberrations, gains of 3q, and losses of 8p, 9p, and 9q predicted survival of MCL patients. A multivariate analysis showed that the gene expression-based proliferation signature was the strongest predictor for shorter survival. However, 3q gains and 9q losses provided prognostic information that was independent of the proliferative activity.

Conclusion: Cyclin D1–positive and –negative MCLs share the same secondary genetic aberrations, supporting the concept that they correspond to the same genetic entity. The integration of genetic information on chromosome 3q and 9q alterations into a proliferation signature-based model may improve the ability to predict survival in patients with MCL.

published online ahead of print at www.jco.org on February 12, 2007.

Supported by the Spanish Comisión Interministerial de Ciencia y Tecnología (CICYT) Grant No. SAF05/5855, Instituto de Salud Carlos III, Red Temática de Cáncer (Grant No. G03/10), Red temática limfomas (Grant No. G03/179; to E.C.); the European Union Contract No. LSHC-CT 2004-503351, the Interdisciplinary Center for Clinical Research of the University of Würzburg, Germany (to A.R.); The Lymphoma Research Foundation, and by a Director's Challenge grant (Grant No. UO1-CA84967) from the National Cancer Institute, Bethesda, MD (to W.C.C.).

Presented as oral communication at the 2006 United States and Canadian Academy of Pathology Annual Meeting, February 11-17, 2006, Atlanta, GA.

I.S., A.Z., and S.B. contributed equally to this work. A.R. and E.C. are the co-senior authors of this work.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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